Technical Field
Compositions and methods for treating and preventing beta (β)-hemolytic streptococcus infections are described herein.
Description of the Related Art
Human pathogens expressing the β-hemolytic phenotype are a heterogeneous group of organisms that includes groups A, C, G, and L streptococci. Group A streptococcal infections result in approximately 500,000 deaths per year worldwide, with invasive infections and rheumatic heart disease as the major contributors to mortality. Group A streptococci (GAS) are ubiquitous human pathogens that cause a wide spectrum of clinical syndromes. The acute infections range from uncomplicated pharyngitis, cellulitis, and pyoderma to life-threatening infections that include necrotizing fasciitis, sepsis, pneumonia, and streptococcal toxic shock syndrome (see, e.g., Bronze et al., Am. J. Med. Sci. 1996; 311:41-54). Mild and even asymptomatic infections can be followed by serious autoimmune diseases; acute rheumatic fever (ARF) and rheumatic heart disease (RHD) are the most significant. Although GAS infections are global in distribution, a distinct dichotomy exists in the burden of GAS infections and their sequelae between economically developed and developing countries of the world. In the United States, Western Europe, and other developed countries, the majority of GAS infections present as uncomplicated pharyngitis or pyoderma.
The greatest overall burden of disease caused by GAS infections is ARF and RHD and serious invasive infections that have a very high mortality rate. The vast majority of afflicted persons live in economically disadvantaged countries. Previous estimates indicated that 350,000 people die each year from complications of RHD, and approximately 12 million people currently suffer from RHD (see, e.g., Carapetis et al., The Lancet Infectious Diseases 2005; 5(11):685-94; Bisno et al., Clin. Infect. Dis. 2005; 41(8):1150-56). An estimated 663,000 cases of invasive infections worldwide result in 163,000 deaths each year. In 2002, the World Health Organization web site listed GAS as the ninth most common single-pathogen cause of death in the world. For the more common mortality-associated pathogens (i.e., tuberculosis, pneumococcus, hepatitis B, Haemophilus influenzae type B, measles, rotavirus), vaccines are available, or very intensive, well-funded vaccine development programs (e.g., HIV, malaria) are ongoing. Recent studies have shown that the prevalence of RHD in children and young adults in developing countries may actually be five times higher than previously predicted (see, e.g., Paar et al., Am. J. Cardiol. 2010; 105(12):1809-14; Marijon et al., N. Engl. J. Med. 2007; 357(5):470-76; Anabwani et al., East Afr. Med. J. 1996; 73(4):215-17; Beaton et al., Circulation 2012; 125(25):3127-32), potentially placing GAS fourth on the list of single-organism causes of death, just behind HIV, tuberculosis, and malaria.
Vaccines designed to prevent the GAS infections that trigger ARF and those that cause serious invasive infections could have a major impact on the health of millions of people, as well as reducing the economic burden of this devastating disease.
Recent taxonomic studies have classified the large-colony group C, G and L streptococcal human pathogens as belonging to the species Streptococcus dysgalactiae subspecies equisimilus (SDSE) to differentiate them from animal pathogens belonging to the same Lancefield groups (see, e.g., Vandamme et al., Int. J. Syst. Bacteriol. 1996; 46(3):774-81). Once considered commensal bacteria of the human microbiome, SDSE have emerged as important human pathogens that cause a spectrum of disease similar to that of group A streptococci (see, e.g., Efstratiou et al., Soc. Appl. Bacteriol. Symp. Ser. 1997; 26: 72S-9S). SDSE are not uncommon colonizers of the human upper respiratory, gastrointestinal, female genital tracts, as well as the skin. These sites most likely represent the portal of entry leading to subsequent infection and serve as the reservoir for human-to-human transmission. The infections range from superficial skin and mucosal infections to life-threatening bacteremia and toxic shock syndrome. SDSE has been associated with outbreaks of pharyngitis in children (see, e.g., Gerber et al., Pediatrics 1991; 87(5): 598-603) and is an established cause of acute post-streptococcal glomerulonephritis (see, e.g., Reid H A, Vet. Rec. 1985; 117(24): 641). Although a potential etiologic role for SDSE in acute rheumatic fever has been proposed (see, e.g., Haidan et al., Lancet 2000; 356(9236):1167-79), a convincing study has not yet been performed.
Recent epidemiologic studies have defined the prominent role of SDSE in serious human infections, the incidence of which equals or exceeds that caused by GAS (see, e.g., Broyles et al., Clin. Infect. Dis. 2009; 48(6):706-12). The pathogenesis of SDSE infections is mediated by virulence determinants that are similar or identical to those expressed by GAS, including streptolysin O, streptolysin S, fibronectin-binding proteins, plasminogen-binding proteins, and pyrogenic exotoxins (see, e.g., Brandt et al., Clin. Infect. Dis. 2009; 49(5):766-72). A major distinguishing factor between human and animal pathogens of group C and G streptococci is that the human pathogens express a surface M protein, which has a function in virulence similar to that of the M protein of GAS (see, e.g., Bisno et al., Infect. Immun. 1987; 55(3):753-57; Collins et al., Infect. Immun. 1992; 60(9): 3689-96).
In view of the increasing incidence of SDSE in human populations and the seriousness of infections caused by SDSE and by group A streptococci, a vaccine that evokes a protective immune response against both group A streptococci and SDSE would provide significant benefit to millions of people.